RE:RE:RE:RE:RE:RE:RE:RE:RE:What's our Oncology Option Worth? "Owing to their high molecular weight and protein-like physicochemical properties, ADCs also suffer from restricted distribution which can prevent these therapies from penetrating some types of solid tumours and limiting their efficacy."
SPCEO1 wrote: Sorry to be so ignorant, but is that good or bad?
jfm1330 wrote: I made a huge mistake here. Thera's peptide is not 15 kDa, but around 1.5 kDa. So it is around 100 times smaller than a monoclonal antibody like those use in ADCs, so it's 7.6 drug molecules for a ADC like Trodelvy versus 760 drug molecules, on mass basis, for Thera's peptide, linker weight excluded. Including the linker weight, the difference would be more like 500 times. By chance I am rereading myself...
jfm1330 wrote: I did not research ADCs a lot, but what I know is that rate of internalization vary a lot depending on the targeted antigen and this process is much slower than with PDCs. In the case of Sortilin, it is a receptor whose role is to internalize what is binding to it, they call it a scavenger receptor. So the rate of internalization is likely to be much higher and faster when compared with ADCs. Also, having two drug molecules on a 15 kDa peptide, is a much higher ratio that having 7.6 drug molecules on a 150 kDa protein.
One important thing I found about ADCs is this:
It is critical to consider that in the patient, the distribution of the target antigen in tumors, as determined by currently available immunohistochemical assays, are often quite different from preclinical models. Most preclinical host animals do not express the target antigen, so the delivery of the ADC to the implanted tumor is not confounded by biodistribution of the ADC to normal host tissues. Furthermore, in patients, the expression of target antigen on the membrane surface of tumor cells has important characteristics that can affect delivery and the binding of the ADC. These include relative membranous and cytosolic expression, the orientation and polarity of the target antigen, and disparate expression on apical, basal lateral, or circumferential cellular surfaces, depending upon the antigen. Moreover, there exists a noteworthy heterogeneity of target antigen expression among adjacent tumor cells, and this can meaningfully affect antitumor activity. The assay selection and cutoff values for scoring potentially sensitive tumor cells is a science unto itself and requires sophisticated input from pathologists experienced in this field before it can be scaled up for clinical trials or validated as a companion diagnostic. For most tumor target antigens that are targets for ADCs, the antigen must be present for antitumor activity, but expression alone does not predict antitumor activity. This has been observed in countless preclinical models and clinical studies. As discussed in the following, the selection of the payload is inextricably related to the tumor indications that express the target antigen.